Agmatine Abrogates Tacrolimus-Induced Testicular Injury in Rats

Background/Objectives: Tacrolimus is an immunosuppressant drug widely used to prevent organ transplant rejection. Preclinical and clinical studies report that tacrolimus has destructive impacts on the male reproductive system owing to the induction of oxidative stress and inflammation. This study aimed at examining defensive impacts of agmatine against tacrolimus-induced testicular toxicity in rats. Methods: Male Wistar rats were randomly divided into six groups and treated based on the experimental design for 14 days. By the end of this study, blood samples were obtained to measure testosterone and luteinizing hormone. Also, both testes were removed for molecular analysis and histopathological examinations. Results: Agmatine administration increased serum levels of testosterone and luteinizing hormone and ameliorated all histopathological and toxicological changes induced by tacrolimus. Agmatine administration attenuated tacrolimus-induced oxidative stress as evidenced by the reduction of malondialdehyde content and inducible nitric oxide synthase expression and the elevation of reduced glutathione. This was parallel to the restoration of nuclear factor erythroid 2-related factor2 and hemeoxygenase-1 expression. Moreover, agmatine decreased the expressions of nuclear factor kappa B and interleukin-17. Agmatine also decreased the cell death revealed by decreased caspase-3 expression and increased expression of the antiapoptotic marker Bcl-2 in a dose-dependent manner. The antioxidant, anti-inflammatory, and antiapoptotic effects of agmatine were explained by increased expression of sirtuin-1. Conclusions: agmatine effectively attenuated testicular injuries induced by tacrolimus and enhanced spermatogenesis. This protective effect of agmatine might be mediated via the upregulation of sirtuin-1 expression that in turn restores oxidative status and regulates nuclear factor erythroid 2-related factor2/nuclear factor kappa B/Bcl-2 signaling.